PCT application PCT/JP2010/062631, published as WO2011/013668 and filed as a continuation-in-part in the United States as U.S. Ser. No. 13/359,281, now U.S. Pat. Nos. 8,652,476 and 9,439,961, describes an improved method to treat cerebral infarction or ischemia in humans by administering a combination of a thrombolytic intervention and an inhibitor of VEGF-RST during the acute stage of the cerebral ischemic event which is considered to be within 6 hours after the onset of the cerebral infarction. This extends the window for treatment from 3 hours to 6 hours.
Supplying an agent that inhibits VEGF-RST ameliorates the hemorrhagic impact of a thrombolytic agent within the enhanced time window for such treatment. This treatment expands the eligible population for thrombolytic therapy, including expanding the time window in which the benefits of administering a thrombolytic outweighs the risks. These documents, however, indicate the dosage level of the VEGF-RST inhibitor is not restricted and suggests high dosages for inhibitors that are anti-VEGF antibodies—in the range of those used to treat cancer.
Studies with regard to such protocols have been published. Zhang, Z. G., et al., J. Clin. Invest. (2000) 106:829-838 administered antibody that binds VEGF early (1 hour) and late (48 hours) after stroke induction in a rat model. Using a Harvard pump (Harvard Apparatus; South Natick, Mass., USA), rhVEGF165 (Genentech Inc., San Francisco, Calif., USA) was infused intravenously to rats at a dose of 1 mg/kg over a 4-hour interval. Early administration was deleterious while late administration was beneficial. The dose level of antibody against VEGF required for ameliorating the toxicity of tPA was based on a polyclonal antibody RB-222: Kanazawa, M., et al., J Cereb Blood Flow Metab (2011) 31:1461-74. A later study was also based on polyclonal antiserum and shows attenuation of BBB disruption by regulating expression of MMP. Zhang, H-T., et al., Mol Med Rep. (2017) 15:57-64.
The time of the onset of cerebral infarction is typically difficult to determine as the subject is not under medical supervision at that time. In addition, presence of a disrupted blood-brain barrier (BBB) in a subject with embolic stroke is a risk factor for hemorrhage after thrombolysis. As described by the present inventors in WO2015/138974, determination of both severity and the period of disturbance of BBB integrity can be accomplished by employing a marker for BBB integrity that is present in the blood. A suitable marker is described in a paper by Marchi, N., et al., Res. Neurol. Neurosci. (2002) 20:1-13, in their corresponding U.S. Pat. Nos. 7,144,708 and 6,884,591 and their later PCT application published as WO2012/154889. These documents describe methods for diagnosing blood-brain barrier permeability in a subject comprising measuring the total level of S100B or its homodimer in the blood wherein elevated levels of S100B or its homodimer indicate BBB permeability. See also Zhou, S., et al., Neurolog. Res. (2016) 38:327-332.
A variety of thrombolytic interventions is described in the literature as is a variety of methods to inhibit VEGF-RST. For example, the thrombolytic intervention may include a plasminogen activator such as tissue plasminogen activator (tPA), urokinase, streptokinase or their analogs, other plasminogen activators such as that derived from vampire bats, or from fungi, such as SMTP-7 or mechanical destruction or removal of the embolus. The inhibitor of VEGF-RST may be a specific binding partner for VEGF or VEGF-R or a compound that inhibits the release of VEGF from platelets or a compound that disrupts signal transduction from activated VEGF-R, such as a tyrosine kinase inhibitor.
The most severe strokes also benefit the most from thrombolytic therapy. However, severe strokes are also at higher risk for disruption of the BBB, with tPA exacerbating that disruption. Accordingly, thrombolytics like tPA are currently used in only a few percent of stroke patients due to the risk of hemorrhage, which is exacerbated when given more than 3 hours after the stroke. With adjunct therapy available to reduce the toxicity of tPA, the patient population that can benefit from such treatment is considerably increased. This extends to patients with “wakeup” stroke as recent studies have shown that typically the stroke occurs just before waking. Rubin, M. W., et al, The Neuro Hospitalist (2015) 5:161-172.
Currently, the assessment of appropriateness of tPA use is made following a CT scan at the hospital, resulting in substantial delay in treatment compared to the optimal early administration of thrombolytic agents. In studies using an ambulance equipped with a portable CT scanner to reduce the delay in diagnosis, substantial reduction in the time required to select thrombolytic intervention was achieved over standard of care, with no increase in adverse events; Walter, S., Lancet Neurology (2012) 11:397-404; Ebinger, M., JAMA (2014) 311:1622-1631. While this work has established the utility of early intervention based on improved diagnostic technology, the cost of equipping all ambulances with a CT scanner is prohibitive. The development of an assay that is suitable for point of care that provides comparable early diagnosis of the potential for tPA to be beneficial creates an opportunity for treating a substantial fraction of stroke patients in an ambulance, prior to arrival at the hospital. The present invention facilitates ambulance based treatment. With this improved diagnostic method, the use of thrombolytic agents in patients resulting in desirable therapeutic effects, may increase from less than 5% of putative stroke patients to more than 25%.
The above documents, and all others cited herein are incorporated by reference.